Nadiminty Nagalakshmi, Lou Wei, Lee Soo Ok, Mehraein-Ghomi Farideh, Kirk Jason S, Conroy Jeffrey M, Zhang Haitao, Gao Allen C
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Clin Cancer Res. 2006 Mar 1;12(5):1420-30. doi: 10.1158/1078-0432.CCR-05-1849.
The high prevalence of osteoblastic bone metastases in prostate cancer involves the production of osteoblast-stimulating factors by prostate cancer cells. Prostate-specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serologic marker for prostate cancer. In this study, we examined the role of PSA in the induction of osteoblast differentiation.
Human cDNA containing a coding region for PSA was transfected into human osteosarcoma SaOS-2 cells. SaOS-2 cells were also treated with exogenously added PSA. We evaluated changes in global gene expression using cDNA arrays and Northern blot analysis resulting from expression of PSA in human osteosarcoma SaOS-2 cells.
SaOS-2 cells expressing PSA had markedly up-regulated expression of genes associated with osteoblast differentiation including runx-2 and osteocalcin compared with the controls. Consistent with these results, the stable clones expressing PSA showed increased mineralization and increased activity of alkaline phosphatase in vitro compared with controls, suggesting that these cells undergo osteoblast differentiation. We also found that osteoprotegerin expression was down-regulated and that the receptor activator of NF-kappaB ligand expression was up-regulated in cells expressing PSA compared with controls.
Modulation of the expression of osteogenic genes and alteration of the balance between osteoprotegerin-receptor activator of NF-kappaB ligand by PSA suggests that PSA produced by metastatic prostate cancer cells may participate in bone remodeling in favor of the development of osteoblastic metastases in the heterogeneous mixture of osteolytic and osteoblastic lesions. These findings provide a molecular basis for understanding the high prevalence of osteoblastic bone metastases in prostate cancer.
前列腺癌中骨母细胞性骨转移的高发生率与前列腺癌细胞产生成骨细胞刺激因子有关。前列腺特异性抗原（PSA）是前列腺癌细胞独特产生的一种丝氨酸蛋白酶，是前列腺癌的重要血清学标志物。在本研究中，我们检测了PSA在诱导成骨细胞分化中的作用。
将含有PSA编码区的人cDNA转染到人骨肉瘤SaOS-2细胞中。还用外源添加的PSA处理SaOS-2细胞。我们使用cDNA阵列和Northern印迹分析评估了人骨肉瘤SaOS-2细胞中PSA表达导致的全局基因表达变化。
与对照相比，表达PSA的SaOS-2细胞中与成骨细胞分化相关的基因（包括runx-2和骨钙素）的表达明显上调。与这些结果一致，表达PSA的稳定克隆在体外与对照相比显示出矿化增加和碱性磷酸酶活性增加，表明这些细胞经历了成骨细胞分化。我们还发现，与对照相比，表达PSA的细胞中骨保护素表达下调，核因子κB受体激活剂配体表达上调。
PSA对成骨基因表达的调节以及骨保护素-核因子κB受体激活剂配体之间平衡的改变表明，转移性前列腺癌细胞产生的PSA可能参与骨重塑，有利于在溶骨性和成骨性病变的异质混合物中发生骨母细胞性转移。这些发现为理解前列腺癌中骨母细胞性骨转移的高发生率提供了分子基础。
